NRG1/ErbB4介导γ振荡异常在脓毒症相关性脑病中的作用及机制

Sepsis associated-encephalopathy (SAE) is a research hotspot in critical care medicine. Our previous study confirmed that sepsis animals displayed cognitive dysfunction, which was accompanied by abnormal PV interneuron and γ oscillations, but restoration of PV interneurons reversed these abnormities, suggesting a critical role of PV interneurons in SAE. Based on the finds that 1) the dynamic balance of inhibition-excitation between PV interneurons and pyramid neurons is an essential neural network for the performance of cognitive function. 2) γ oscillations result from the synchronized activity of PV interneurons mediate the performance of cognitive function. 3) the distribution of ErbB4 is largely restricted to PV interneurons and the activation NRG1/ErbB4 signaling facilitates the formation of excitatory synapses on PV interneurons and then up-regulates the power of γ oscillations. Therefore, we tested the hypothesis that: sepsis → inhibition of NRG1/ErbB4 signaling → reduction of excitatory synapses on PV interneurons → impaired function of PV interneurons → decreased power of γ oscillations → neural network hypersynchrony → cognitive impairments. To test this hypothesis, we will apply behavioral tests, electrophysiology, molecular biology, and transgenic techniques to study the novel mechanism underlying the sepsis-induced cognitive impairments at multiple levels of behavior, neural network, cell function, synapse formation, and molecular signaling. The proposed studies will provide new scientific concepts of SAE, which could lead to the prevention and treatment of SAE.

脓毒症相关性脑病（SAE）是危重病医学研究的热点课题。我们前期研究证实：脓毒血症小鼠认知功能损伤伴海马微清蛋白（PV）中间神经元及γ振荡异常，但恢复PV中间神经元可以逆转上述异常，提示PV中间神经元在介导SAE中起重要作用。鉴于1）微清蛋白（PV）中间神经元与锥体细胞间“抑制-兴奋动态平衡”是维持大脑正常功能的关键；2）PV中间神经元同步电活动产生的γ振荡是学习记忆等认知功能的基础；3）NRG1与主要表达于PV中间神经元的ErbB4结合，促进PV中间神经元兴奋性突触形成，从而正向调控γ振荡。因而，推测脓毒血症通过影响NRG1/ErbB4从而降低PV中间神经元兴奋性，进而导致PV中间神经元功能及γ振荡异常是SAE发病的关键机制。本项目拟采用行为学、电生理、转基因、分子生物学等技术，从整体行为—神经网络—细胞—突触—分子多层次揭示SAE的神经环路机制，为其治疗提供新的理论依据和靶点。

脓毒症相关性脑病（SAE）是脓毒症患者严重的中枢神经系统并发症，主要表现为学习记忆受损、注意力不集中等。SAE严重危害人类的身心健康并增加患者的死亡率，给家庭和社会带来极为沉重的负担。然而，SAE的发病机制至今仍不清楚。.本项目通过盲肠结扎穿孔模型与LPS等方法建立SAE，探讨其可能的发病机制。主要内容有：（1）通过建立CLP动物模型，探讨NRG1/ErbB4是否介导SAE的发病及其可能的机制；（2）探讨海马β2微球蛋白是否参与SAE发病及其可能机制；（3）通过LPS等方法建立免疫耐受，探讨后期CLP打击对小鼠认知功能的影响，探索免疫耐受对脑功能的影响及其机制。.通过以上研究我们得出一些重要结果和关键数据：（1） NRG1/ErbB4通过影响微清蛋白中间神经元功能，进而影响神经功能网络功能，从而介导SAE发病；（2）在CLP动物模型中，β2微球蛋白负性调控学习记忆；（3）证实早期建立的免疫记忆对后期脓毒症有神经保护作用。在本项目资助下，已发表SCI论文2篇，本项目的实验结果可望为SAE的防治提供新思路与实验依据。